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SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion

View ORCID ProfileAkatsuki Saito, View ORCID ProfileHesham Nasser, Keiya Uriu, Yusuke Kosugi, Takashi Irie, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, View ORCID ProfileJumpei Ito, Jiaqi Wu, Seiya Ozono, View ORCID ProfileKenzo Tokunaga, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Takasuke Fukuhara, Ryoko Kawabata, Takemasa Sakaguchi, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Kazuhisa Yoshimura, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Akifumi Takaori-Kondo, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, View ORCID ProfileKei Sato
doi: https://doi.org/10.1101/2021.06.17.448820
Akatsuki Saito
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
2Center for Animal Disease Control, University of Miyazaki, Miyazaki 8892192, Japan
3Graduate School of Medicine and Veterinary Medicine, University of Miyazaki, Miyazaki 8892192, Japan
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  • ORCID record for Akatsuki Saito
Hesham Nasser
4Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
5Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia 41511, Egypt
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Keiya Uriu
6Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Yusuke Kosugi
6Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Takashi Irie
7Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Kotaro Shirakawa
8Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Kenji Sadamasu
9Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Izumi Kimura
6Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Jumpei Ito
6Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
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Jiaqi Wu
10Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 2591193, Japan
11CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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Seiya Ozono
12Department of Pathology, National Institute of Infectious Diseases, Tokyo 1628640, Japan
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Kenzo Tokunaga
12Department of Pathology, National Institute of Infectious Diseases, Tokyo 1628640, Japan
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Erika P Butlertanaka
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
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Yuri L Tanaka
1Department of Veterinary Science, Faculty of Agriculture, University of Miyazaki, Miyazaki 8892192, Japan
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Ryo Shimizu
4Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
13Graduate School of Medical Sciences, Kumamoto University, Kumamoto 8600811, Japan
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Kenta Shimizu
14Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido 0608638, Japan
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Takasuke Fukuhara
14Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Hokkaido 0608638, Japan
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Ryoko Kawabata
7Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Takemasa Sakaguchi
7Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 7348551, Japan
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Isao Yoshida
9Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Hiroyuki Asakura
9Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Mami Nagashima
9Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Kazuhisa Yoshimura
9Tokyo Metropolitan Institute of Public Health, Tokyo 1690073, Japan
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Yasuhiro Kazuma
8Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Ryosuke Nomura
8Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Yoshihito Horisawa
8Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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Akifumi Takaori-Kondo
8Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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So Nakagawa
10Department of Molecular Life Science, Tokai University School of Medicine, Kanagawa 2591193, Japan
11CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp KeiSato@g.ecc.u-tokyo.ac.jp
Terumasa Ikeda
4Division of Molecular Virology and Genetics, Joint Research Center for Human Retrovirus infection, Kumamoto University, Kumamoto 8600811, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp KeiSato@g.ecc.u-tokyo.ac.jp
Kei Sato
6Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan
11CREST, Japan Science and Technology Agency, Saitama 3220012, Japan
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  • For correspondence: so@tokai.ac.jp ikedat@kumamoto-u.ac.jp KeiSato@g.ecc.u-tokyo.ac.jp
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Summary

During the current SARS-CoV-2 pandemic, a variety of mutations have been accumulated in the viral genome, and at least five variants of concerns (VOCs) have been considered as the hazardous SARS-CoV-2 variants to the human society. The newly emerging VOC, the B.1.617.2 lineage (delta variant), closely associates with a huge COVID-19 surge in India in Spring 2021. However, its virological property remains unclear. Here, we show that the B.1.617 variants are highly fusogenic and form prominent syncytia. Bioinformatic analyses reveal that the P681R mutation in the spike protein is highly conserved in this lineage. Although the P681R mutation decreases viral infectivity, this mutation confers the neutralizing antibody resistance. Notably, we demonstrate that the P681R mutation facilitates the furin-mediated spike cleavage and enhances and accelerates cell-cell fusion. Our data suggest that the P681R mutation is a hallmark characterizing the virological phenotype of this newest VOC, which may associate with viral pathogenicity.

Highlights

  • P681R mutation is highly conserved in the B.1.617 lineages

  • P681R mutation accelerates and enhances SARS-CoV-2 S-mediated fusion

  • Promotion of viral fusion by P681R mutation is augmented by TMPRSS2

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵15 Twitter: @SystemsVirology

  • ↵17 Lead Contact

  • Conflict of interest: The authors declare that no competing interests exist.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted June 17, 2021.
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SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion
Akatsuki Saito, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Takashi Irie, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, Jumpei Ito, Jiaqi Wu, Seiya Ozono, Kenzo Tokunaga, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Takasuke Fukuhara, Ryoko Kawabata, Takemasa Sakaguchi, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Kazuhisa Yoshimura, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Akifumi Takaori-Kondo, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, Kei Sato
bioRxiv 2021.06.17.448820; doi: https://doi.org/10.1101/2021.06.17.448820
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SARS-CoV-2 spike P681R mutation enhances and accelerates viral fusion
Akatsuki Saito, Hesham Nasser, Keiya Uriu, Yusuke Kosugi, Takashi Irie, Kotaro Shirakawa, Kenji Sadamasu, Izumi Kimura, Jumpei Ito, Jiaqi Wu, Seiya Ozono, Kenzo Tokunaga, Erika P Butlertanaka, Yuri L Tanaka, Ryo Shimizu, Kenta Shimizu, Takasuke Fukuhara, Ryoko Kawabata, Takemasa Sakaguchi, Isao Yoshida, Hiroyuki Asakura, Mami Nagashima, Kazuhisa Yoshimura, Yasuhiro Kazuma, Ryosuke Nomura, Yoshihito Horisawa, Akifumi Takaori-Kondo, The Genotype to Phenotype Japan (G2P-Japan) Consortium, So Nakagawa, Terumasa Ikeda, Kei Sato
bioRxiv 2021.06.17.448820; doi: https://doi.org/10.1101/2021.06.17.448820

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